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Background: Stem-cell-based, tissue engineered transplants might offer new therapeutic options for patients, including children, with failing organs. The reported replacement of an adult airway using stem cells on a biological scaffold with good results at 6 months supports this view. We describe the case of a child who received a stem-cell-based tracheal replacement and report findings after 2 years of follow-up.Methods: A 12-year-old boy was born with long-segment congenital tracheal stenosis and pulmonary sling. His airway had been maintained by metal stents, but, after failure, a cadaveric donor tracheal scaffold was decellularised. After a short course of granulocyte colony stimulating factor, bone marrow mesenchymal stem cells were retrieved preoperatively and seeded onto the scaffold, with patches of autologous epithelium. Topical human recombinant erythropoietin was applied to encourage angiogenesis, and transforming growth factor β to support chondrogenesis. Intravenous human recombinant erythropoietin was continued postoperatively. Outcomes were survival, morbidity, endoscopic appearance, cytology and proteomics of brushings, and peripheral blood counts.Findings: The graft revascularised within 1 week after surgery. A strong neutrophil response was noted locally for the first 8 weeks after surgery, which generated luminal DNA neutrophil extracellular traps. Cytological evidence of restoration of the epithelium was not evident until 1 year. The graft did not have biomechanical strength focally until 18 months, but the patient has not needed any medical intervention since then. 18 months after surgery, he had a normal chest CT scan and ventilation-perfusion scan and had grown 11 cm in height since the operation. At 2 years follow-up, he had a functional airway and had returned to school.Interpretation: Follow-up of the first paediatric, stem-cell-based, tissue-engineered transplant shows potential for this technology but also highlights the need for further research.Funding: Great Ormond Street Hospital NHS Trust, The Royal Free Hampstead NHS Trust, University College Hospital NHS Foundation Trust, and Region of Tuscany. [ABSTRACT FROM AUTHOR]

Despite the recognition that epilepsy can substantially disrupt memory, there are few published accounts of whether and how this disruption varies across different types of memory and/or different types of epilepsy. This review explores four main questions: (1) Are working, episodic and semantic memory differentially affected by epilepsy? (2) Do various types of epilepsy, and their treatment, have different, specifiable effects on memory? (3) Are the usual forms of neuropsychological assessments of memory - many or most designed for other conditions - appropriate for patients with epilepsy? (4) How can research on epilepsy contribute to our understanding of the neuroscience of memory? We conclude that widespread and multifactorial problems are seen in working memory in all patient groups, while patients with temporal lobe epilepsy seem particularly prone to episodic memory deficit, and those with frontal lobe epilepsy to executive function deficits that may in turn impair semantic control. Currently, it is difficult to make individual patient predictions about likely memory deficits based on seizure aetiology and type, but it is possible to guide and tailor neuropsychological assessments in an individualised way. We make recommendations for future directions in validating and optimising neuropsychological assessments, and consider how to approach effective shared decision making about the pros and cons of seizure treatment strategies, especially at crucial educational stages such as adolescence., Competing Interests: Declaration of competing interest No authors have any conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Beetroot powder, a popular athletic supplement high in nitrates, purportedly enhances exercise performance. However, recent incidents during breath-hold swims in Air Force Special Warfare training, associated with beetroot powder use, raise safety concerns. Two cases of hypoxic events prompt discussion on interactions between beetroot supplementation and cardiovascular responses to breath-hold diving, suggesting a risk for blackout. Beetroot-induced vasodilation may counteract normal cardiovascular responses during swimming, emphasizing the need for further research to quantify risks. With inconsistent dosing and lack of standardized recommendations, heightened awareness of these risks is crucial for informed decision-making regarding beetroot supplements, especially in tactical athletes., Competing Interests: Declaration of interest statement The authors disclose no conflict of interest., (Published by Elsevier Ltd.)

Background: Acute kidney injury (AKI) is common among hospitalized patients. However, the contribution of social determinants of health (SDOH) to AKI risk remains unclear. This study evaluated the association between neighborhood measures of SDOH and AKI development and recovery during hospitalization., Methods: This is a retrospective cohort study of adults without end-stage kidney disease admitted to a large southern U.S. healthcare system from 10/2014 to 9/2017. Neighborhood SDOH measures included: 1) Socioeconomic status: Area Deprivation Index (ADI) scores, 2) Food access: Low Income Low Access (LILA) scores, 3) Rurality: Rural Urban Commuting Area (RUCA) scores, and (4) Residential segregation: dissimilarity and isolation scores. The primary study outcome was AKI based on serum creatinine (SCr)-KDIGO criteria. Our secondary outcome was lack of AKI recovery (requiring dialysis or elevated SCr at discharge). The association of SDOH measures with AKI was evaluated using generalized estimating equation models adjusted for demographics and clinical characteristics., Results: Among 26,769 patients, 26% developed AKI during hospitalization. Compared with those who did not develop AKI, those who developed AKI were older (median 60 vs. 57 years), more commonly men (55% vs. 50%), and more commonly self-identified as Black (38% vs. 33%). Patients residing in most disadvantaged neighborhoods (highest ADI tertile) had 10% (95%CI: 1.02-1.19) greater adjusted odds of developing AKI during hospitalization than counterparts in least disadvantaged areas (lowest ADI tertile). Patients living in rural areas had 25% higher adjusted odds of lack of AKI recovery by hospital discharge (95% CI: 1.07, 1.46). Food access and residential segregation were not associated with AKI development or recovery., Conclusions: Hospitalized patients from the most socioeconomically disadvantaged neighborhoods and from rural areas had higher odds of developing AKI and not recovering from AKI by hospital discharge, respectively. A better understanding of the mechanisms underlying these associations is needed to inform interventions to reduce AKI risk during hospitalization among disadvantaged populations., (Copyright © 2024 by the American Society of Nephrology.)

Severe staffing shortages have emerged as a prominent threat to maintaining usual standards of care during the COVID-2019 pandemic. In dire settings of crisis capacity, healthcare systems assume the ethical duty to maximise aggregate population-level benefit of existing resources. To this end, existing plans for rationing mechanical ventilators and intensive care unit beds in crisis capacity focus on selecting individual patients who are most likely to survive and prioritising these patients to receive scarce resources. However, staffing capacity is conceptually different from availability of these types of discrete resources, and the existing strategy of identifying and prioritising patients with the best prognosis cannot be readily adapted to fit this real-world scenario. We propose that two alternative approaches to staffing resource allocation offer a better conceptual fit: (1) prioritise the worst off : restrict access to acute care services and hospital admission for patients at relatively low clinical risk and (2) prioritise staff interventions with high near-term value : universally restrict selected interventions and treatments that require substantial staff time and/or energy but offer minimal near-term patient benefit. These strategies-while potentially resulting in care that deviates from usual standards-support the goal of maximising the aggregate benefit of scarce resources in crisis capacity settings triggered by staffing shortages. This ethical framework offers a foundation to support institutional leaders in developing operationalisable crisis capacity policies that promote fairness and support healthcare workers., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Inflammation has been proposed as a crucial player in neurodegeneration, including Frontotemporal Dementia (FTD). A few studies on sporadic FTD lead to inconclusive results, whereas large studies on genetic FTD are lacking. The aim of this study is to determine cytokine and chemokine plasma circulating levels in a large cohort of genetic FTD, collected within the GENetic Frontotemporal dementia Initiative (GENFI)., Methods: Mesoscale technology was used to analyse levels of 30 inflammatory factors in 434 plasma samples, including 94 Symptomatic Mutation carriers [(SMC); 15 with mutations in Microtubule Associated Protein Tau (MAPT) 34 in Progranulin (GRN) and 45 in Chromosome 9 Open Reading Frame (C9ORF)72], 168 Presymptomatic Mutation Carriers (PMC; 34 MAPT, 70 GRN and 64 C9ORF72) and 173 Non-carrier Controls (NC)]., Results: The following cytokines were significantly upregulated (P<0.05) in MAPT and GRN SMC versus NC: Tumor Necrosis Factor (TNF)α, Interleukin (IL)-7, IL-15, IL-16, IL-17A. Moreover, only in GRN SMC, additional factors were upregulated, including: IL-1β, IL-6, IL-10, IL-12/IL-23p40, eotaxin, eotaxin-3, Interferon γ-induced Protein (IP-10), Monocyte Chemotactic Protein (MCP)4. On the contrary, IL-1α levels were decreased in SMC compared with NC. Significantly decreased levels of this cytokine were also found in PMC, independent of the type of mutation. In SMC, no correlations between disease duration and cytokine and chemokine levels were found. Considering NfL and GFAP levels, as expected, significant increases were observed in SMC as compared to NC. These differences in mean values remain significant even when stratifying symptomatic patients by the mutated gene (P<0.0001). Considering instead the levels of NfL, GFAP, and the altered inflammatory molecules, no significant correlations emerged., Conclusion: We showed that inflammatory proteins are upregulated in MAPT and GRN SMC, with some specific factors altered in GRN only, whereas no changes were seen in C9ORF72 carriers. Notably, only IL-1α levels were decreased in both SMC and PMC, independent of the type of causal mutation, suggesting common modifications occurring in the preclinical phase of the disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Mucopolysaccharidosis (MPS) type IVA is a rare lysosomal storage disorder caused by aberrations of the N-acetyl-galactosamine-6-sulfatase (GALNS) enzyme. MPS IVA is associated with a wide gamut of respiratory and airway disorders that manifest in a continuum of severity. In individuals exhibiting severe phenotypic expression, terminal stages of the disease frequently culminate in life-threatening, critical airway obstruction. These manifestations of end-stage disease are engendered by an insidious progression of multi-level airway pathologies, comprising of tracheomalacia, stenosis, tortuosity and 'buckling'. Historically, the management of end-stage airway disease has predominantly leaned towards palliative modalities. However, contemporary literature has posited that the potential benefits of tracheal resection with aortopexy, performed under cardiopulmonary bypass (CPB), may offer a promising therapeutic option. In this context, we report on outcomes from patients undergoing a novel approach to tracheal resection that is combined with manubrial resection, leading to improved airway calibre, obviating the requisition for CPB., Results: In this study, seven patients with severe MPS IVA exhibited clinical symptoms and radiological evidence indicative of advanced airway obstruction. All patients had a tracheal resection with a partial upper manubriectomy via transcervical approach, which did not require CPB. The surgical cohort consisted of 5 females and 2 males, the median age was 16 years (range 11-19) and the median height was 105.6cm (range 96.4-113.4). Postoperatively, significant improvements were seen in forced expiratory volume in 1 second (FEV1), with a mean increase of 0.68 litres (95% CI: 0.45-0.91; SD: 0.20). Notably, other spirometry variables also showed meaningful improvements, providing evidence of positive treatment effects. Furthermore, there were no major long-term complications, and the procedure resulted in a significant enhancement in patient-reported domains using PedsQL (version 4.0)., Conclusions: This study represents the largest case series to date, on tracheal resection in patients with severe MPS IVA. Our findings demonstrate the effectiveness of the transcervical approach with partial manubriectomy for improving respiratory function and quality of life for individuals with advanced airway obstruction. Tracheal resection presents a promising treatment modality for severe cases of MPS IVA. Successful outcomes rely on meticulous multidisciplinary assessment, judicious decision-making, and appropriate timing of tracheal surgery. Further research and long-term follow-up studies are warranted to validate the long-term efficacy and safety of this approach., (© 2024. The Author(s).)

Introduction: The Special Warfare Training Wing and Special Warfare Human Performance Support Group (HPSG; all-co-authors) were established in fiscal year (FY) 2019 to consolidate and oversee all Air Force Special Warfare (AFSPECWAR) training and provide embedded medical and human performance support to candidates with the goal of improving graduation rates and the longevity of the AFSPECWAR operator. The purpose of this manuscript is to assess the impact of the HPSG on AFSPECWAR graduation rates, musculoskeletal injury (MSKI) incidence, and cost., Materials and Methods: Graduation rates, MSKI incidence (including incidence density and cumulative incidence probability), and MSKI-related health care costs were assessed across all AFSPECWAR training pipelines spanning 8 FYs 2015-22, including Indoctrination, Assessment, and Selection Courses (Selection); Tactical Air Control Party (TACP); Special Tactics (ST), and Guardian Angel (GA)., Results: A total of 5,728 distinct candidates were assessed over the time frame. There were significant decreases in attrition when comparing the HPSG era (FY 19-22) with the prior 4-year period for the ST (47% vs. 82% graduates) and TACP (34% vs. 41% graduates) training pipelines. The corresponding Selection (36% graduates) and GA (80% graduates) pipeline attrition rates remained stable. MSKI incidence rates (both incidence density and cumulative incidence probability) overall were not significantly different when comparing the pre-HPSG and HPSG time frames; however, they varied between the two time frames by course. GA candidates had a decrease in MSKI during the apprentice course in the HPSG era compared with the pre-HPSG era (2.4-1.0 cases per 100 trainee weeks; P < .001), which corresponds to a nearly 20% reduction in the cumulative incidence probability (i.e., proportion of trainees injured) after 10 weeks of course. For ST and TACP courses, however, significantly increased incidence of MSKI was observed when comparing the two time frames (P < .001), while for Selection courses, the rates remained stable. A significant reduction in the cost of MSKI-related management (62% total relative value units, 83% total costs) was observed., Conclusion: The impact of the HPSG on attrition, MSKI incidence, and cost-of-care was not consistent across all training pipelines; however, taken together, there were no increases in attrition, and the cost of MSKI management was significantly lower., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2024. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Current clustering of multimorbidity based on the frequency of common disease combinations is inadequate. We estimated the causal relationships among prevalent diseases and mapped out the clusters of multimorbidity progression among them., Methods: In this cohort study, we examined the progression of multimorbidity among 190 diseases among over 500,000 UK Biobank participants over 12.7 years of follow-up. Using a machine learning method for causal inference, we analyzed patterns of how diseases influenced and were influenced by others in females and males. We used clustering analysis and visualization algorithms to identify multimorbidity progress constellations., Results: We show the top influential and influenced diseases largely overlap between sexes in chronic diseases, with sex-specific ones tending to be acute diseases. Patterns of diseases that influence and are influenced by other diseases also emerged (clustering significance P au  > 0.87), with the top influential diseases affecting many clusters and the top influenced diseases concentrating on a few, suggesting that complex mechanisms are at play for the diseases that increase the development of other diseases while share underlying causes exist among the diseases whose development are increased by others. Bi-directional multimorbidity progress presents substantial clustering tendencies both within and across International Classification Disease chapters, compared to uni-directional ones, which can inform future studies for developing cross-specialty strategies for multimorbidity. Finally, we identify 10 multimorbidity progress constellations for females and 9 for males (clustering stability, adjusted Rand index >0.75), showing interesting differences between sexes., Conclusion: Our findings could inform the future development of targeted interventions and provide an essential foundation for future studies seeking to improve the prevention and management of multimorbidity., (© 2024. The Author(s).)

Selective activation of the M 4 muscarinic acetylcholine receptor subtype offers a novel strategy for the treatment of psychosis in multiple neurological disorders. Although the development of traditional muscarinic activators has been stymied due to pan-receptor activation, muscarinic receptor subtype selectivity can be achieved through the utilization of a subtype of a unique allosteric site. A major challenge in capitalizing on this allosteric site to date has been achieving a balance of suitable potency and brain penetration. Herein, we describe the design of a brain penetrant series of M 4 selective positive allosteric modulators (PAMs), ultimately culminating in the identification of 21 ( PF-06852231, now CVL-231/emraclidine), which is under active clinical development as a novel mechanism and approach for the treatment of schizophrenia.

Objectives: The objective was to measure health-related quality of life (HRQoL) of children following treatment of all-cause tracheomalacia with aortopexy., Methods: Children ≥5 years and parents of children <18 years who had undergone aortopexy completed the Paediatric Quality of Life Inventory (PedsQL4.0). Scores were compared to published norms., Results: Completed questionnaires were received from 35 parents (65%) and 10 children (38%). Median age at aortopexy was 9.8 months (1 month-12.7 years) and median years of follow-up was 2.6 (4 months-6.9 years). Children who completed questionnaires had a median age of 8.4 (5.7-13.4) years. Parent and child-reported total PedsQL scores were 69.61 (SD : 19.74), and 63.15 (SD : 20.40) respectively. Half of parents and 80% of children reported scores suggesting poor HRQoL outcomes. Parent-reported total, physical and psycho-social scores were lower than those of healthy children and those with acute illness but comparable to children with chronic health conditions and cardiovascular disease. Similarly, children themselves reported comparable total scores to children with chronic illness but child-reported psycho-social scores were lower in the aortopexy group than any other group. There was no association between PedsQL scores and cause of malacia, age or time since aortopexy. The presence of complex congenital comorbidities had a significant (p < 0.05) impact on HRQoL scores., Conclusions: Following aortopexy children remain at risk of poor HRQoL, especially those with complex comorbidities. HRQoL reported by both parent and child provides important insight into the lives of children following this procedure. Further longitudinal and qualitative study are required to better understand this complex group., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Introduction: Each year, thousands of individuals enlist in the Department of the Air Force (DAF), with some seeking to become DAF Special Warfare (SW) candidates. This study aimed to compare the anthropomorphic and physical fitness characteristics between these groups during fiscal years (FYs) 2019-2023., Methods:  The sample includes male candidates below the age of 30 who attended the DAF basic military training (BMT) from FY2019 to 2023 (N = 119,415). Initial physical fitness testing was conducted during week 1 of BMT. Physical fitness results, height, weight, and body mass index (BMI) were compared between the two cohorts. A two-way analysis of variance was performed to analyze the effects of group (SW and non-SW) and FY on mean anthropomorphic and physical fitness test variables. Dependent variables were evaluated for homogeneity of variance using Levene's test and for normality using the Shapiro-Wilk test. The Tukey-Kramer test was employed for post hoc analyses with a threshold for statistical significance of α < 0.05., Results:  The cohort of SW recruits displayed superior physical fitness results across all FYs (p < 0.001) with the exception of FY2021. They were significantly taller and heavier, and had a higher BMI when compared to non-SW DAF BMT recruits (p < 0.001). Mean values for maximum push-ups and sit-ups for SW recruits were significantly lower in FY2021 (p < 0.001) and not significantly different from non-SW recruits. Additionally, run times for both SW- and non-SW-bound recruits during FY2022 and FY2023 were significantly slower than previous years., Conclusions:  These findings can be used to establish a baseline for anthropometric and physical fitness profiles of incoming SW and non-SW DAF BMT recruits that may inform clinicians, human performance professionals, and military training leaders with information necessary to guide future research and physical fitness policy., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. 59th Medical Wing Human Research Protection Program issued approval FWH20240087E. Study procedures received an exempt determination (reference no. FWH20240087E) and were approved through the 59th Medical Wing Human Research Protection Program, 59th Medical Wing Office of Clinical Research Support, Joint Base San Antonio-Lackland, TX. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Mata et al.)

The glymphatic system is an emerging target in neurodegenerative disorders. Here, we investigated the activity of the glymphatic system in genetic frontotemporal dementia with a diffusion-based technique called diffusion tensor image analysis along the perivascular space. We investigated 291 subjects with symptomatic or presymptomatic frontotemporal dementia (112 with chromosome 9 open reading frame 72 [ C9orf72 ] expansion, 119 with granulin [ GRN ] mutations and 60 with microtubule-associated protein tau [ MAPT ] mutations) and 83 non-carriers (including 50 young and 33 old non-carriers). We computed the diffusion tensor image analysis along the perivascular space index by calculating diffusivities in the x -, y - and z -axes of the plane of the lateral ventricle body. Clinical stage and blood-based markers were considered. A subset of 180 participants underwent cognitive follow-ups for a total of 640 evaluations. The diffusion tensor image analysis along the perivascular space index was lower in symptomatic frontotemporal dementia (estimated marginal mean ± standard error, 1.21 ± 0.02) than in old non-carriers (1.29 ± 0.03, P = 0.009) and presymptomatic mutation carriers (1.30 ± 0.01, P < 0.001). In mutation carriers, lower diffusion tensor image analysis along the perivascular space was associated with worse disease severity ( β = -1.16, P < 0.001), and a trend towards a significant association between lower diffusion tensor image analysis along the perivascular space and higher plasma neurofilament light chain was reported ( β = -0.28, P = 0.063). Analysis of longitudinal data demonstrated that worsening of disease severity was faster in patients with low diffusion tensor image analysis along the perivascular space at baseline than in those with average ( P = 0.009) or high ( P = 0.006) diffusion tensor image analysis along the perivascular space index. Using a non-invasive imaging approach as a proxy for glymphatic system function, we demonstrated glymphatic system abnormalities in the symptomatic stages of genetic frontotemporal dementia. Such measures of the glymphatic system may elucidate pathophysiological processes in human frontotemporal dementia and facilitate early phase trials of genetic frontotemporal dementia., Competing Interests: The authors have no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Exertional heat stroke (EHS), which presents with extreme hyperthermia and alteration to the central nervous system, disproportionately affects the military, where warfighters are expected to perform in all types of environmental conditions. Because of an incomplete understanding of individualized recovery from EHS, there are several shortcomings with the current guidance on return to duty (RTD) following an EHS. The purpose of this manuscript is to provide an updated literature review of best practices for return to duty following EHS to guide decision making regarding EHS and explore areas of future research for medical staff who work with warfighters., Materials and Methods: A literature review related to EHS in both athlete and military populations, as well as any existing guidelines for RTD, was conducted using PubMed and Covidence., Results: Twenty-one articles were identified for this updated review on EHS and RTD, with recommendations focused during and after an EHS event, as well as the role of heat tolerance testing (HTT)., Conclusions: EHS has a high morbidity and mortality rate if not treated rapidly. Because the extent of end-organ damage is dependent on the amount of time that the individual is hyperthermic, rapid diagnosis via rectal thermometry, and efficient cooling methods are imperative to the wellbeing of EHS patients. Following EHS, gradual RTD recommendations within the limits of operational demand should be implemented to reduce the risk for a subsequent heat injury event. While many versions of HTT, most notably the Israeli Defense Force (IDF) protocol, have been created to guide RTD recommendations, a universal assessment for heat tolerance has yet to be adopted. As such, medical personnel should apply a multifactorial approach to ensure safe RTD., (© The Association of Military Surgeons of the United States 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The hallmark of epidermolysis bullosa (EB) is fragile attachment of epithelia due to genetic variants in cell adhesion genes. We describe 16 EB patients treated in the ear, nose, and throat department of a tertiary pediatric hospital linked to the United Kingdom's national EB unit between 1992 and 2023. Patients suffered a high degree of morbidity and mortality from laryngotracheal stenosis. Variants in laminin subunit alpha-3 (LAMA3) were found in 10/15 patients where genotype was available. LAMA3 encodes a subunit of the laminin-332 heterotrimeric extracellular matrix protein complex and is expressed by airway epithelial basal stem cells. We investigated the benefit of restoring wild-type LAMA3 expression in primary EB patient-derived basal cell cultures. EB basal cells demonstrated weak adhesion to cell culture substrates, but could otherwise be expanded similarly to non-EB basal cells. In vitro lentiviral overexpression of LAMA3A in EB basal cells enabled them to differentiate in air-liquid interface cultures, producing cilia with normal ciliary beat frequency. Moreover, transduction restored cell adhesion to levels comparable to a non-EB donor culture. These data provide proof of concept for a combined cell and gene therapy approach to treat airway disease in LAMA3-affected EB., Competing Interests: Declaration of interests The authors declare no competing interests. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. For the purpose of open access, the corresponding author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Children infected with SARS-CoV-2 rarely progress to respiratory failure. However, the risk of mortality in infected people over 85 years of age remains high. Here we investigate differences in the cellular landscape and function of paediatric (<12 years), adult (30-50 years) and older adult (>70 years) ex vivo cultured nasal epithelial cells in response to infection with SARS-CoV-2. We show that cell tropism of SARS-CoV-2, and expression of ACE2 and TMPRSS2 in nasal epithelial cell subtypes, differ between age groups. While ciliated cells are viral replication centres across all age groups, a distinct goblet inflammatory subtype emerges in infected paediatric cultures and shows high expression of interferon-stimulated genes and incomplete viral replication. In contrast, older adult cultures infected with SARS-CoV-2 show a proportional increase in basaloid-like cells, which facilitate viral spread and are associated with altered epithelial repair pathways. We confirm age-specific induction of these cell types by integrating data from in vivo COVID-19 studies and validate that our in vitro model recapitulates early epithelial responses to SARS-CoV-2 infection., (© 2024. The Author(s).)

Advocates for improved equity in kidney transplants in the United States have recently focused their efforts on initiatives to increase referral for transplant evaluation. However, because donor kidneys remain scarce, increased referrals are likely to result in an increasing number of patients proceeding through the evaluation process without ultimately receiving a kidney. Unfortunately, the process of referral and evaluation can be highly resource-intensive for patients, families, transplant programs, and payers. Patients and families may incur out-of-pocket expenses and be required to complete testing and treatments that they might not have chosen in the course of routine clinical care. Kidney transplant programs may struggle with insufficient capacity, inefficient workflow, and challenging programmatic finances, and payers will need to absorb the increased expenses of upfront pretransplant costs. Increased referral in isolation may risk simply transmitting system stress and resulting disparities to downstream processes in this complex system. We argue that success in efforts to improve access through increased referrals hinges on adaptations to the pretransplant process more broadly. We call for an urgent re-evaluation and redesign at multiple levels of the pretransplant system in order to achieve the aim of equitable access to kidney transplantation for all patients with kidney failure., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD)., Methods: Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI)., Results: The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales., Discussion: Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely., Highlights: The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS).No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale.Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains.A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales., Competing Interests: The authors declare that they have no competing interests. Author disclosures are available in the supporting information., (© 2024 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Dust is a sink for many semi-volatile compounds including flame retardants of the organophosphate ester (OPE) and brominated flame-retardant (BFR) classes. Given the large amount of time that we spend indoors, our exposure to these compounds via dust is of significant interest. Here, we present a novel microextraction approach to determine quantitative levels of selected OPEs and BFRs sampled from residential air filters from HVAC systems using a small volume of solvent. Dust samples (25 mg) is extracted with 1 mL of hexane/acetone (50/50, v/v). Upon solvent extraction of these HVAC dust samples, the analytes (TCPP, TDCPP, TPHP, T24DtBPP, TBBPA, and TriBBPA) were quantified via gas chromatography-mass spectrometry (GC/MS) or liquid chromatography-mass spectrometry (LC/MS). The methods for extracting these compounds from HVAC dust samples are detailed here with extensive method validation data to demonstrate accuracy and precision of these methods. •Dust is a sink for many semi-volatile compounds, including novel or emerging indoor pollutants like the organophosphate ester flame retardant T24DtBPP.•Here, a small amount of dust (25 mg) is extracted with a small volume of solvent (1 mL hexane and acetone) prior to analysis via chromatographic separation and mass spectrometric detection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Exertional heat illness remains a constant threat to the athlete, military service member, and laborer. Recent increases in the number and intensity of environmental heat waves places these populations at an ever increasing risk and can be deadly if not recognized and treated rapidly. For this reason, it is extremely important for medical providers to guide athletes, service members, and laborers in the implementation of awareness, education, and measures to reduce or mitigate the risk of exertional heat illness. Within the past 2 decades, a variety of wearable technology options have become commercially available to track an estimation of core temperature, yet questions continue to emerge as to its use, effectiveness, and practicality in athletics, the military, and the workforce. There is a paucity of data on the accuracy of many of these newer devices in the setting of true heat stroke physiology, and it is important to avoid overreliance on new wearable technology. Further research and improvement of this technology are critical to identify accuracy in the diagnosis and prevention of EHI., (© 2024 American Academy of Physical Medicine and Rehabilitation.)

Objectives: Exertional heat stroke (EHS) remains a significant health concern while training in hot environments, prompting the development of noninvasive wearable technology for monitoring estimated core temperature (ECT). The objective of this study was to review the effectiveness of an ECT device during elite military training by providing a case series of individuals who developed EHS., Methods: This is a retrospective study of EHS cases during high-intensity training while wearing the ECT device, Zephyr Bioharness TM . Data was collected from January 2021 through September 2021 at the Air Force Special Warfare Training pipeline in San Antonio, TX. Rectal temperatures of EHS diagnoses, defined by central nervous system (CNS) dysfunction and rectal temperature approaching or >40°C (104°F), were compared to ECT reading via Zephyr Bioharness TM . Incidence rates and psychometric properties were calculated using R package., Results: A total of 47,058 daily peak ECT measurements were collected among 1,364 trainees. A total of 499 trainees flagged as potential EHS by Zephyr Bioharness TM reading >39.7°C (103.5°F). The incidence of confirmed EHS was 0.8/1000 person-months. Of the 10 confirmed EHS cases (9 males, 1 female; age = 23.4 ± 2.7 yrs; BMI = 25 ± 2; body fat = 13 ± 5%), 8 trainees had a peak ECT reading below 39.7°C which resulted in a sensitivity of 20%, specificity of 98.9%, positive likelihood ratio (LR) of 18.93 (95% Confidence Interval [CI] 5.5-65.6), and a negative LR of 0.81 (95% CI 0.6-1.1)., Conclusion: ECT had substantial false positive and negative rates. Further studies are needed to validate this technology in other populations, and the algorithm used in this device needs to be refined to better capture the environmental and physical requirements in the special operations population.

Introduction: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive impairment in visuospatial and perceptual function linked to atrophy of the occipito-parietal cortex. Besides the salient visual impairment, several studies have documented subtle changes in language may also be present. Sentence repetition is a highly constrained linguistic task involving multiple linguistic and cognitive processes and have been shown to be impaired in other AD spectrum disorders, with little consensus on its relevance in PCA. This aim of this study was to further delineate the linguistic and cognitive features of impaired language in PCA using a sentence repetition task., Method: Seven PCA patients and 16 healthy controls verbally repeated 16 sentences from the Boston Diagnostic Aphasia Examination. Responses were transcribed orthographically and coded for accuracy (percentage accuracy; percentage Correct Information Units; Levenshtein Distance) and for temporal characteristics (preparation duration (ms); utterance duration (ms); silent pause duration (ms); speech duration (ms); dysfluency duration (ms)). The potential modulating effects of attentional control and working memory capacity were explored., Results: PCA patients showed lower overall accuracy with retained semantic content of the sentences, and lower phonological accuracy. Temporal measures revealed longer preparation and utterance duration for PCA patients compared to controls, alongside longer speech duration but comparable dysfluency duration. PCA patients also showed comparable silent pause duration to controls. Attentional control, measured using the Hayling sentence completion task, predicted accuracy of sentence repetition., Discussion: The findings suggest that sentence repetition is impaired in PCA and is characterized by phonological, response planning and execution difficulties, underpinned in part by attentional control mechanisms. The emerging profile of language impairment in PCA suggests vulnerability of similar cognitive systems to other Alzheimer's syndromes, with subtle differences in clinical presentation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ahmed, Caswell, Butler and Bose.)

Objectives: Work is an under-recognized social determinant of health. There is limited research describing US wildland firefighter (WFF) workforce demographics or how to work associates with WFF health behaviors. In this study researchers characterized a WFF cohort and tested hypotheses that WFFs used tobacco, alcohol, and sugar-sweetened beverages (SSBs) differently over the course of the fire season and that different fire crews may exhibit different behavior patterns., Methods: Researchers collected data in the field with 6 WFF crews during 2 consecutive fire seasons (2018 and 2019). WFF crews completed questionnaires before and after each season. WFFs with an initial preseason questionnaire and at least 1 follow-up questionnaire were included (n = 138). Descriptive statistics summarized WFFs' baseline demographic, employment, and health characteristics. Linear mixed models were used to test for changes in WFFs' substance use over time and assess crew-level differences. A meta-analysis of WFF longitudinal studies' population characteristics was attempted to contextualize baseline findings., Results: WFFs were predominately male, less than 35 yr of age, non-Hispanic White, and had healthy weight. Smokeless tobacco use and binge drinking were prevalent in this cohort (52% and 78%, respectively, among respondents). Longitudinal analyses revealed that during the fire season WFFs' use of tobacco and SSBs increased and the number of days they consumed alcohol decreased. Crew-level associations varied by substance. The meta-analysis was not completed due to cross-study heterogeneity and inconsistent reporting., Discussion: WFF agencies can promote evidence-based substance use prevention and management programs and modify working conditions that may influence WFF stress or substance use., (Published by Oxford University Press on behalf of The British Occupational Hygiene Society 2024.)

Background: The Genetic Frontotemporal Initiative Staging Group has proposed clinical criteria for the diagnosis of prodromal frontotemporal dementia (FTD), termed mild cognitive and/or behavioral and/or motor impairment (MCBMI). The objective of the study was to validate the proposed research criteria for MCBMI-FTD in a cohort of genetically confirmed FTD cases against healthy controls., Methods: A total of 398 participants were enrolled, 117 of whom were carriers of an FTD pathogenic variant with mild clinical symptoms, while 281 were non-carrier family members (healthy controls (HC)). A subgroup of patients underwent blood neurofilament light (NfL) levels and anterior cingulate atrophy assessment., Results: The core clinical criteria correctly classified MCBMI vs HC with an AUC of 0.79 (p < 0.001), while the addition of either blood NfL or anterior cingulate atrophy significantly increased the AUC to 0.84 and 0.82, respectively (p < 0.001). The addition of both markers further increased the AUC to 0.90 (p < 0.001)., Conclusions: The proposed MCBMI criteria showed very good classification accuracy for identifying the prodromal stage of FTD., (© 2024. The Author(s).)

Background: Long non-coding RNAs (lncRNAs) play crucial roles in gene regulation and are implicated in neurodegenerative diseases, including frontotemporal dementia (FTD). However, their expression patterns and potential as biomarkers in genetic FTD involving Chromosome 9 Open Reading Frame (C9ORF72), Microtubule Associated Protein Tau (MAPT), and Progranulin (GRN) genes are not well understood., Objective: This study aimed to profile the expression levels of lncRNAs in peripheral blood mononuclear cells collected within the GENetic Frontotemporal dementia Initiative (GENFI)., Methods: Fifty-three lncRNAs were analyzed with the OpenArray Custom panel, in 131 patients with mutations in C9ORF72, MAPT, and GRN, including 68 symptomatic mutation carriers (SMC) and 63 presymptomatic mutation carriers (PMC), compared with 40 non-carrier controls (NC)., Results: Thirty-eight lncRNAs were detectable; the relative expression of NEAT1 and NORAD was significantly higher in C9ORF72 SMC as compared with NC. GAS5 expression was instead significantly lower in the GRN group versus NC. MAPT carriers showed no significant deregulations. No significant differences were observed in PMC. Disease duration did not correlate with lncRNA expression., Conclusions: NEAT1 and NORAD are upregulated in C9ORF72 SMC and GAS5 levels are downregulated in GRN SMC, underlining lncRNAs' relevance in FTD and their potential for biomarker development. Further validation and mechanistic studies are crucial for clinical implications.

Background: With the arrival of disease-modifying treatments, it is mandatory to find new cognitive markers that are sensitive to Alzheimer's disease (AD) pathology in preclinical stages., Objective: To determine the utility of a newly developed Learning and Associative Memory face test: LAM test. This study examined the relationship between AD cerebrospinal fluid (CSF) biomarkers and performance on LAM test, and assessed its potential clinical applicability to detect subtle changes in cognitively healthy subjects at risk for AD., Methods: We studied eighty cognitively healthy volunteers from the Valdecilla cohort. 61% were women and the mean age was 67.34 years (±6.416). All participants underwent a lumbar puncture for determination of CSF biomarkers and an extensive neuropsychological assessment, including performance on learning and associative memory indices of the LAM-test after 30 min and after 1 week, and two classic word lists to assess verbal episodic memory: the Rey Auditory Verbal Learning Test (RAVLT) and the Free and Cued Selective Reminding Test (FCSRT). We analyzed cognitive performance according to amyloid status (A+ versus A-) and to ATN model (A-T-N-; A+T-N-; A+T+N-/A+T+N+)., Results: Performance on the LAM-test was significantly correlated with CSF Aβ ratio. A+ participants performed worse on both learning (mean difference = 2.19, p = 0.002) and memory LAM measures than A- (mean difference = 2.19, p = 0.004). A decline in performance was observed along the Alzheimer's continuum, with significant differences between ATN groups., Conclusions: Our findings suggest that LAM test could be a useful tool for the early detection of subjects within the AD continuum, outperforming classical memory tests.

Advocacy and policy change are powerful levers to improve quality of care and better support patients on home dialysis. While the kidney community increasingly recognizes the value of home dialysis as an option for patients who prioritize independence and flexibility, only a minority of patients dialyze at home in the United States. Complex system-level factors have restricted further growth in home dialysis modalities, including limited infrastructure, insufficient staff for patient education and training, patient-specific barriers, and suboptimal physician expertise. In this article, we outline trends in home dialysis use, review our evolving understanding of what constitutes high-quality care for the home dialysis population (as well as how this can be measured), and discuss policy and advocacy efforts that continue to shape the care of US patients and compare them with experiences in other countries. We conclude by discussing future directions for quality and advocacy efforts., (Copyright © 2023 by the American Society of Nephrology.)

Background: Plasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia., Methods: Blood samples from 693 participants in the GENetic Frontotemporal Dementia Initiative study were analysed using a multiplexed antibody array targeting 158 proteins., Results: We found 13 elevated proteins in symptomatic mutation carriers, when comparing plasma levels from people diagnosed with genetic FTD to healthy non-mutation controls and 10 proteins that were elevated compared to presymptomatic mutation carriers., Conclusion: We identified plasma proteins with altered levels in symptomatic mutation carriers compared to non-carrier controls as well as to presymptomatic mutation carriers. Further investigations are needed to elucidate their potential as fluid biomarkers of the disease process., (© 2023. The Author(s).)